This application is a 371 of PCT/EP00/06563 Jul. 11, 2000.
Preparation of 4-cyano-2-aminomethylthiazole
The present invention relates to a novel process for preparing 2-aminomethyl-4-cyanothiazole.
Syntheses for preparing 2-aminomethylthiazoles which are substituted in the 4 position by an electron-withdrawing group, such as a carboxylic acid or a carboxylic acid derivative, for example an ester, an amide or a thioamide, have been described in the literature.
The key step of the synthesis sequence is the construction of the thiazole ring. In the customary literature syntheses, the thiazole ring is obtained by reacting a thioamide with a bromopyruvic acid derivative (1) G. Videnov, D. Kaiser, C. Kempter, G. Jung, Angew. Chem. Int. Ed. Engl. 35 (1996), 1503; (2) Y. Nakamura, C. Shin, K. Umemura, J. Yoshimura, Chem. Lett. (1992), 1005; (3) J. A. Sowinski, P. L. Toogwood, J. Org. Chem. 61 (1996), 7671; (4) M. North, G. Pattenden, Tetrahedron 46 (1990), 8267; (5) U. Schmidt, Synthesis 1987, 233; (6) WO 98/6741.
The thioamides used for this purpose are obtained, for example, by reacting an amide with Lawessons"" reagent (1), (2), (3), or by reacting an aminonitrile with H2S (7) K. P. Moder, F. R. Busch, D. C. Richter, Org. Prep. Proced. Int. 24 (1992), 66; G. Li, P. M. Warner, D. J. Jebaratnam, J. Org. Chem. 61 (1961), 778; T. P. Holler, F. Q. Ruan, A. Spaltenstein, P. B. Hopkins, J. Org. Chem. 54 (1989), 4570; T. P . Culbertson, J. M. Dornagala, P. Peterson, S. Bongers, J. B. Nichols, J. Heterocycl. Chem. 24 (1987), 1509; H. Moser, A. Flin, A. Steiger, A. Eschenmesser, Helv. Chim. Acta 69 (1986), 1224.
The processes described in the literature are in most cases only suitable for small batches on a laboratory scale. They employ protective groups which, when used on an industrial scale, would increase preparation costs owing to the high cost of the starting materials. Furthermore, in the case of the synthesis of the thioamides with reaction with H2S, industrial implementation of the process is made difficult owing to high environmental and safety requirements. The synthesis of the thioamides with Lawesson""s reagent on an industrial scale is unattractive for economical reasons, owing to the high cost of the starting materials. Furthermore, it has been found that these procedures, when the reaction is conducted on a pilot plant scale, do not give the yields that have been described, and/or can only be realized with very high technical expense.
In addition to the intermolecular cyclizations mentioned, intramolecular cyclizations of an N-(hydroxyethyl)thioamide under Mitsunobo conditions have also been described in the literature (8) C. Shin, A. Ito, K. Okumura, Y. Nakamura, Chem. Left. (1995), 45. However, this method also entails the abovementioned disadvantages.
If it were easily accessible industrially, 2-aminomethyl-4-cyanothiazole would be an interesting intermediate for preparing serine protease inhibiting low-molecular-weight substances (for example thrombin inhibitors). Such thrombin inhibitors are mentioned, for example, in WO 9806741. Moreover, 2-aminomethyl-4-cyanothiazole can be used for preparing other thrombin inhibitors and their prodrugs such as, for example, N-(ethoxycarbonylmethytene)-(D)cyclohexylaianyl-3,4-dehydro-prolyl-[2-(4-hydroxyamidino)thiazole]methylamide hydrochloride.
It is an object of the present invention to provide a process for preparing 2-aminomethyl-4-cyanothiazole, thus making available this synthesis building block cost efficiently for other syntheses.
We have found that this object is achieved by a novel way of constructing the thiazole skeleton which makes the 4-cyano-2-methylthiazole building block industrially accessible. 
where R1 is branched or straight-chain C1-C10-alkyl or 
where n=0, 1 or 2 and R2 is branched or straight-chain C1-C10-alkyl or C1-C4-alkoxy or C1-C4-dialkylamino. Preferred substituents are xe2x80x94OCH3, OCH2CH3, N(CH3)2, N(C2H5)2, CH3, C2H5, C3H7.
Here, the thiazole ring is obtained by reacting an aminonitrile with L-cysteine, giving the thiazolidine, followed by its oxidative aromatization.
Thiazole syntheses by oxidation of thiazolidines or thiazolanes are known from the literature; however, they have only been described on a laboratory scale. Frequently, these oxidations are carried out using manganese dioxide. However, this variant gives only moderate yields (9) Y. Hamada, K. Kohda, T. Shioiri, Tetrahedron Lett. 25 (1984), 5303. Better yields are obtained by using perbenzoic acid esters in the presence of copper salts (10) F. X. Tavares, A. I. Meyers, Tetrahedron Lett. 35 (1994), 6803; (11) A. I. Meyers, F.X. Tavares, J. Org. Chem. 61 (1996), 8207. Almost quantitative conversion is obtained in the presence of bromochloroform and DBU (12) D. R. Williams, P. D. Lowder, Y. G. Yu, D. A. Brooks, Tetrahedron Lett. 38 (1997), 331. This reaction is characterized by particularly mild reaction conditions. However, this synthesis, too, has only been carried out on a gram scale.
The preparation of a thiazolidine or thiazolane starting from a cysteine derivative has only rarely been mentioned in the literature. Examples are known where a cysteine ester has been reacted with aminoaldehydes to give the thiazolane (3), (4), which is then converted into the thiazole via the thiazolidine intermediate. However, xcex1-aminoaldehydes are not very stable. Moreover, they are not commercially available, and they therefore have to be prepared from the corresponding amino acids by multi-step processes.
In addition, thiazolidine syntheses are known where the thiazolidine is obtained by reacting the cysteine derivative with imido esters (3), (4), (10), (13) K. Inami, T. Shiba, Bull. Chem. Soc. Jpn. 58 (1985), 352. However, imido esters are likewise not commercially available and have to be synthesized by a multi-step process, for example from an aminonitrile.
According to the invention, the thiazolidine was synthesized from an aminonitrile, with quantitative conversion. The reaction of the cysteine ester hydrochlorides, in particular the methyl and ethyl esters, with the protected aminoacetonitrile is carried out in an inert solvent, for example in cyclic or open-chain ethers, such as THF, dioxane, DME, in acetonitrile, DMF, or chlorinated hydrocarbons such as CH2Cl2, CHCl3 or in toluene, or in an alcoholic medium (C1-C6-alcohol, preferably isopropanol, ethanol or methanol) in the presence of a base, such as, for example, NEt3, morpholine, pyridine, lutidine, DMAP, DBU, DBN (preferably triethylamine). The thiazolidine can then be oxidized quantitatively to the corresponding thiazole. The oxidation is likewise carried out in inert solvents, such as, for example, chlorinated hydrocarbons, toluene or cyclic and open-chain ethers.
Organic amines, such as NEt3, morpholine, pyridine, DMAP (dimethylaminopyridine) and lutidine serve as base.
In both steps, the crude products can be employed directly in the next step without costly purification.
The next step in the synthesis sequence according to the invention is the aminolysis of the ester to give the amide. The aminolysis can be carried out both in aqueous medium and in alcoholic ammonia solution. It is possible to use alcoholic NH3 solutions (for example in MeOH, EtOH, iPrOH), but also aqueous NH3 solutions (for example 25% strength).
In aqueous NH3 solutions, higher NH3 excesses are required; for this reason, preference is given to alcoholic NH3 solutions, owing to the higher space-time yield. The process according to the invention is characterized in that the reaction can be carried out in highly concentrated form using the crude thiazolecarboxylic acid ester. If the process is carried out on an industrial scale, this results in a good space-time yield.
The conversion into the 2-aminomethyl-4-cyanothiazole (VIII) or (Ia) and (Ib) can then be carried out in a simple manner by dehydratization using, for example, trifluoroacetic anhydride, and subsequent gentle removal of the BOC protective group.
The process according to the invention is characterized in that it can be carried out in a simple manner, without costly purification. All the essential reaction steps proceed with quantitative or almost quantitative yields. The costs of the starting materials are low, and the use of toxic substances (in particular gases) can be dispensed with.
Likewise unexpected was the aminolysis of the thiazolecarboxylic acid ester with aqueous ammonia to give the thiazolecarboxamide. Preference is given to using an excess of at least 5 molar equivalents of NH3, in particular of at least 10 molar equivalents of NH3. It is also possible to use alcohol as solubilizer. However, in the series of the alcohols, the yields with methanol were higher than those with isopropanol. If alcohols are used, it is possible to carry out the reaction with small amounts of NH3.
The thiazolecarboxylic acid ester can be obtained in crystalline form. By hydrolyzing the ester with, for example, aqueous sodium hydroxide solution, followed by pH-controlled addition of acid, it is also possible to prepare in a simple manner and with good yields the corresponding BOC-protected thiazolecarboxylic acid by this route.
For the synthesis on an industrial scale, it is advantageous to prepare the thiazolecarboxamide in a one-pot process, without isolating the ester. Starting from cysteine ester, it is thus possible to prepare the crystalline amide in a yield of  greater than 50%, at little technical expense.
The present invention relates to a process for preparing 2-aminomethyl-4-cyanothiazole and its salts of the formulae Ia and Ib 
in which
n=1 or 2 and
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and
for n=2, X is sulfate,
which can be obtained by introducing the tert-butyloxycarbonyl protective group (BOC) on the nitrogen of the aminoacetonitrile, followed by reaction with cysteine ester and oxidation to the corresponding thiazole-4-carboxylic acid ester and further conversion into the thiazole-4-carboxamide and finally the 4-cyanothiazole derivative.
The 4-cyanothiazoles VII and VIII are novel.
Using this process, the intermediates IV and V can be converted advantageously, without further work-up, into the respective subsequent product.
The 4-cyanothiazole salt VIII, which is embraced by the formula Ia, can be reacted under pH-controlled conditions with bases to give the salt-free form of the formula Ib.
The invention furthermore relates to processes for preparing 2-aminomethyl-4-cyanothiazole and its salts of the formulae Ia and Ib 
in which
n=1 or 2 and
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and,
for n=2, X is sulfate. In the process according to the invention, the aminonitrile of the formula II 
is stirred with a cysteine ester of the formula III 
in which R1 is branched or linear C1-10-alkyl or 
where n=0, 1 or 2 and R2 is branched or straight-chain C1-C10-alkyl or C1-C4-alkoxy or C1-C4-dialkylamino, in an inert solvent in the presence of a base at from 0xc2x0 C. to 80xc2x0 C. until the reaction has essentially proceeded to completion.
The cysteine ester is preferably present as hydrochloride.
Moreover, according to the invention, the resulting thiazolidine IV 
can be oxidized in an inert solvent.
The resulting thiazolecarboxylic acid ester of the formula V 
in which R1 is as defined above is stirred in an alcohol R2OH, in which R2 is branched or linear C1-8-alkyl, HOxe2x80x94CH2xe2x80x94CH2xe2x80x94, HOxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or C1-4-alkyl-Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, at from 0xc2x0 C. to 40xc2x0 C. with from 1 to 50 molar equivalents of NH3 until the reaction has essentially proceeded to completion.
Following the steps above, the process can be carried out without isolation of the intermediates.
The thiazolecarboxamide of the formula VI 
can be filtered off as a solid.
Furthermore, the amide VI can subsequently be dehydrated to give the BOC-protected 4-cyanothiazole of the formula VII 
and the BOC protective group can be removed.
Furthermore, the invention relates to a process for preparing the compound of the formula V 
in which the aminonitrile of the formula II 
is stirred with a cysteine ester of the formula III 
in which R1 is branched or linear C1-10-alkyl or 
where n=0, 1 or 2 and R2 is branched or straight-chain C1-C10-alkyl or C1-C4-alkoxy or C1-C4-dialkylamino in an inert solvent in the presence of a base at from 0xc2x0 C. to 80xc2x0 C. until the reaction has essentially proceeded to completion.
If appropriate, when preparing the compound of the formula IV 
according to the above process, the resulting thiazolecarboxylic acid ester of the formula V 
in which R1 is as defined above is stirred in an alcohol R2OH at from 0xc2x0 C. to 40xc2x0 C. with from 1 to 50 molar equivalents of NH3 in an aqueous ammonia solution until the reaction has essentially gone to completion.
Furthermore, the invention relates to compounds of the formulae Ia and Ib 
in which
n=1 or 2 and
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and
for n=2, X is sulfate,
and to the compound of the formula VII 